Hélène M. Faessel

Single-Dose Pharmacokinetics of Varenicline, a Selective Nicotinic Receptor Partial Agonist, in Healthy Smokers and Nonsmokers

Varenicline is a novel and selective α4β2 nicotinic receptor partial agonist that is under development for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, single‐dose, dose‐escalation study were to determine the clinical pharmacology of single doses of varenicline in healthy smokers and nonsmokers under fed and fasted conditions and to determine the clinical pharmacology of varenicline administered in the morning and in the evening to smokers. Within each subject group, 4 subjects were randomized to varenicline and 2 subjects to placebo. Subjects received one single oral administration of varenicline or placebo: 6 doses (0.01, 0.03, 0.1, 0.3, 1.0, and 3.0 mg) were investigated in nonsmokers and 7 doses in smokers (0.01, 0.03, 0.1, 0.3, 1.0, 3.0, and 10.0 mg). Varenicline was well tolerated after single doses up to 3.0 mg in smokers and 1.0 mg in nonsmokers. Nausea and vomiting at doses above 3.0 mg in smokers and 1.0 mg in nonsmokers were dose limiting. Systemic exposure to varenicline and pharmacokinetic variability were similar between smokers and nonsmokers. Coadministration with food, smoking restriction, and time‐of‐day dosing did not affect the pharmacokinetics of varenicline.

Multiple‐Dose Pharmacokinetics of the Selective Nicotinic Receptor Partial Agonist, Varenicline, in Healthy Smokers

Varenicline is a novel and selective α4β2 nicotinic acetylcholine receptor partial agonist developed for smoking cessation. The primary objectives of this double‐blind, placebo‐controlled, dose‐escalation study were to determine the pharmacokinetics, safety, and tolerability of multiple oral doses of varenicline given as tablets once (1 mg, 2 mg, and 3 mg) or twice (1 mg) daily to healthy adult smokers. Within each dose level, 8 subjects were randomized to varenicline and 4 subjects to placebo. Varenicline was well tolerated at doses up to and including 2 mg daily. Dose‐proportional increases in maximum observed plasma concentrations and area under the plasma concentration‐time curve from time zero to the end of the dosing interval values were observed between the 1‐mg and 2‐mg daily doses of varenicline. Once‐ and twice‐daily dosing resulted, on average, in an approximate 2‐ and 3‐fold increase in varenicline systemic exposure, respectively, compared with single dose. There was no evidence of concentration‐ or time‐dependent changes in the pharmacokinetics of varenicline upon repeat dosing.

A review of the clinical pharmacokinetics and pharmacodynamics of varenicline for smoking cessation.

Varenicline tartrate (Chantix®/Champix®) is a selective partial agonist of the α4β2 nicotinic acetylcholine receptor and is approved as an aid to smoking cessation. The usual oral dosage in adults is 1 mg twice daily for 12 weeks, with an initial titration week. Several clinical pharmacology studies have characterized the pharmacokinetics of varenicline in adult smokers aged 18–55 years, elderly smokers and nonsmokers aged ≥65 years, adolescent smokers aged 12–17 years and subjects with impaired renal function. Varenicline exhibits linear pharmacokinetics following single- and multiple-dose administration of up to 3 mg/day. After oral administration absorption is virtually complete and systemic availability is high. Oral bioavailability is not affected by food or time-of-day dosing; maximum plasma drug concentrations typically occur within 3–4 hours after dosing. Protein binding of varenicline is low (≤20%) and independent of age and renal function. Varenicline is almost exclusively excreted unchanged in urine, primarily through glomerular filtration, with some component of active tubular secretion via human organic cation transporter, hOCT-2. Varenicline does not undergo significant metabolism and is not metabolized by hepatic microsomal cytochrome P450 (CYP) enzymes. Consistent with an elimination half-life of ∼24 hours, steadystate conditions are reached within 4 days of repeat dosing. There are no remarkable differences between smokers and nonsmokers in metabolism or excretion of varenicline. In vitro, varenicline does not inhibit nor induce the activity of the major CYP enzymes.No clinically meaningful pharmacokinetic drug interactions are observed when varenicline is coadministered with the narrow therapeutic index drugs warfarin or digoxin, the smoking cessation therapies bupropion or transdermal nicotine, and the renally secreted drugs cimetidine or metformin. An integrated model-based analysis of varenicline pharmacokinetics across several studies in adult smokers further showed that renal function was the clinically important factor leading to interindividual variability in systemic exposure to varenicline. Although no dose adjustment is required for subjects with mild to moderate renal impairment, a dose reduction to 1 mg/day is indicated for subjects with severe renal insufficiency. After accounting for renal function, there was no apparent effect of age, sex or race on varenicline pharmacokinetics. Varenicline pharmacokinetics in adolescents were generally comparable to those in adults; the bodyweight effect, which resulted in greater exposure in individuals of smaller body size (weighing ≤55 kg), was adequately offset by administration of half the dose recommended in adults. (It is, however, important to note that varenicline is currently not approved for use in smokers aged under 18 years).Exposure-response analyses relating individual-specific drug exposure to clinical responses consistently showed that the end-of-treatment abstinence rate in adult smokers increased linearly with increasing varenicline exposure; the 1 mg twice-daily dose regimen was reliably associated with greater exposure and an increased probability of achieving a stable quit within 1 year from the start of treatment. Nausea was the single most frequently reported adverse event in varenicline clinical trials, with an incidence that was sexrelated and increased with varenicline exposure. In all, the predictable pharmacokinetic properties and straightforward dispositional profile of varenicline simplify its use in clinical practice.

Population pharmacokinetic analysis of varenicline in adult smokers

AIMSnTo characterize the population pharmacokinetics of varenicline and identify factors leading to its exposure variability in adult smokers.nnnMETHODSnData were pooled from nine clinical studies consisting of 1878 subjects. Models were developed to describe concentration-time profiles across individuals. Covariates were assessed using a full model approach; parameters and bootstrap 95% confidence intervals (CI) were estimated using nonlinear mixed effects modelling.nnnRESULTSnA two-compartment model with first-order absorption and elimination best described varenicline pharmacokinetics. The final population parameter estimates (95% CI) were: CL/F, 10.4 l h(-1) (10.2, 10.6); V(2)/F, 337 l (309, 364); V(3)/F, 78.1 l (61.9, 98.9); Q/F, 2.08 l h(-1) (1.39, 3.79); K(a), 1.69 h(-1) (1.27, 2.00); and A(lag), 0.43 h (0.37, 0.46). Random interindividual variances were estimated for K(a)[70% coefficient of variation (CV)], CL/F (25% CV), and V(2)/F (50% CV) using a block covariance matrix. Fixed effect parameters were precisely estimated [most with % relative standard error < 10 and all with % relative standard error < 25], and a visual predictive check indicated adequate model performance. CL/F decreased from 10.4 l h(-1) for a typical subject with normal renal function (CLcr = 100 ml min(-1)) to 4.4 l h(-1) for a typical subject with severe renal impairment (CLcr = 20 ml min(-1)), which corresponds to a 2.4-fold increase in daily steady-state exposure. Bodyweight was the primary predictor of variability in volume of distribution. After accounting for renal function, there was no apparent effect of age, gender or race on varenicline pharmacokinetics.nnnCONCLUSIONSnRenal function is the clinically important factor leading to interindividual variability in varenicline exposure. A dose reduction to 1 mg day(-1), which is half the recommended dose, is indicated for subjects with severe renal impairment.

Pharmacokinetics, Safety, and Tolerability After Single and Multiple Oral Doses of Varenicline in Elderly Smokers

Varenicline is a novel selective α4β2 nicotinic acetylcholine partial agonist developed for smoking cessation. This study investigated the single‐ and multiple‐dose pharmacokinetics, safety, and tolerability of varenicline in elderly (≥ 65 years) smokers. Twenty‐four elderly smokers with normal renal function for their age (estimated creatinine clearance ≥ 70 mL/min) received varenicline 1 mg once daily (n = 8) or placebo (n = 4) for 7 days, or 1 mg twice daily (n = 8) or placebo (n = 4) for 6 days with a single dose on day 7 in a double‐blind, parallel group and placebo‐controlled design. There was no evidence of concentration‐ or time‐dependent changes in varenicline pharmacokinetics upon repeat dosing. Once‐ and twice‐daily dosing was associated with an approximate 2‐fold and 3‐fold increase, respectively, in systemic exposure to varenicline. Varenicline was well tolerated; all adverse events reported were mild to moderate in intensity. Thus, no dose adjustment is necessary based on age alone.

Pharmacokinetics, safety, and tolerability of varenicline in healthy adolescent smokers: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study

BACKGROUNDnVarenicline is approved as an aid to smoking cessation in adults aged > or =18 years.nnnOBJECTIVEnThe goal of this study was to characterize the multiple-dose pharmacokinetics, safety, and tolerability of varenicline in adolescent smokers.nnnMETHODSnThis multicenter, randomized, double-blind, placebo-controlled, parallel-group study enrolled healthy 12- to 16-year-old smokers (> or =3 cigarettes daily) into high-body-weight (>55 kg) and low-body-weight (< or =55 kg) groups. Subjects were randomized to receive 14 days of treatment with a high dose of varenicline, a low dose of varenicline, or placebo. The varenicline doses in the high-body-weight group were 1 mg BID and 0.5 mg BID; the varenicline doses in the low-body-weight group were 0.5 mg BID and 0.5 mg once daily. The apparent renal clearance (CL/F) and volume of distribution (V/F) of varenicline and the effect of body weight on these parameters were estimated using nonlinear mixed-effects modeling.nnnRESULTSnThe high-body-weight group consisted of 35 subjects (65.7% male; 77.1% white; mean age, 15.2 years). The low-body-weight group consisted of 37 subjects (37.8% male; 48.6% white; mean age, 14.3 years). The pharmacokinetic parameters of varenicline were dose proportional over the dose range from 0.5 to 2 mg/d. The CL/F for a 70-kg adolescent was 10.4 L/h, comparable to that in a 70-kg adult. The estimated varenicline V/F was decreased in individuals of small body size, thus predicting a varenicline C(max) approximately 30% greater in low-body-weight subjects than in high-body-weight subjects. In high-body-weight subjects, steady-state varenicline exposure, as represented by the AUC(0-24), was 197.0 ng . h/mL for varenicline 1 mg BID and 95.7 ng . h/mL for varenicline 0.5 mg BID, consistent with values reported previously in adult smokers at the equivalent doses. In low-body-weight subjects, varenicline exposure was 126.3 ng . h/mL for varenicline 0.5 mg BID and 60.1 ng . h/mL for varenicline 0.5 mg once daily, values at the lower end of the range observed previously in adults at doses of 1 mg BID and 0.5 mg BID, respectively. Among high-body-weight subjects, adverse events (AEs) were reported by 57.1% of subjects in both the high- and low-dose varenicline groups and by 14.3% of subjects in the placebo group; among low-body-weight subjects, AEs were reported by 64.3%, 73.3%, and 12.5% of subjects in the high-dose varenicline, low-dose varenicline, and placebo groups, respectively. The most common AEs were nausea, headache, vomiting, and dizziness. Psychiatric AEs that were considered treatment related included abnormal dreams in 2 subjects and mild, transient anger in 1 subject. Of the AEs reported by > or =1 subject in any treatment group, > or =92% were mild in intensity. No subject discontinued the study because of an AE.nnnCONCLUSIONSnVarenicline steady-state exposure in study subjects weighing >55 kg was similar to that observed previously in adults. The body-weight effect on varenicline pharmacokinetics, which resulted in higher exposure in individuals of smaller body size (< or =55 kg), was adequately offset by administration of half the varenicline dose recommended in adults. Varenicline was generally well tolerated during the 14-day treatment period. Clinical Trials Identification Number: NCT00463918.

Lack of Pharmacokinetic and Pharmacodynamic Interactions Between a Smoking Cessation Therapy, Varenicline, and Warfarin: An In Vivo and In Vitro Study1

This study investigated the effect of varenicline on the pharmacokinetics and pharmacodynamics of a single dose of warfarin in 24 adult smokers and compared these findings with data generated using human in vitro systems. Subjects were randomized to receive varenicline 1 mg twice a day or placebo for 13 days and then switched to the alternative treatment after a 1‐week washout period. A single dose of warfarin 25 mg was given on day 8 of each treatment period, and serial blood samples were collected over 144 hours postdose. Pharmacokinetic parameters for both (R)‐ and (S)‐warfarin and international normalized ratio (INR) values were determined. Varenicline was assessed as an inhibitor and inducer of human cytochrome P450 activities using liver microsomes and hepatocytes, respectively. Consistent with the in vitro data, no alteration in human pharmacokinetics of warfarin enantiomers was observed with varenicline treatment. The 90% confidence intervals for the ratios of area under the concentration–time curve from zero hours to infinity and peak plasma concentrations were completely contained within 80% to 125%. Warfarin pharmacodynamic parameters, maximum INR, and the area under the prothrombin (INR)–time curve, were also unaffected by steady‐state varenicline. Concomitant administration of varenicline and warfarin was well tolerated. Consequently, warfarin can be safely administered with varenicline without the need for dose adjustment.

Quantitative Assessment of Exposure–Response Relationships for the Efficacy and Tolerability of Varenicline for Smoking Cessation

Population exposure–response analyses involving ~2,000 cigarette smokers provided an integrated understanding of dose, exposure, patient characteristics, and response relating to the efficacy and tolerability of varenicline for smoking cessation. Full models with a linear function of area under the concentration–time curve at steady state AUC(0–24)ss and covariate effects on the baseline probability of response were constructed. Logistic regression results consistently showed that the end‐of‐treatment abstinence rate increased with increasing varenicline exposure, from 38% at 0.5 mg b.i.d. to 56% at 1 mg b.i.d. (vs. 22% for placebo). Baseline smoking status and age were predictive of smoking cessation, whereas race and gender showed little or no influence. Nausea was the most common adverse event, with an incidence that was gender‐related and that increased with varenicline exposure; at a dosage of 1 mg b.i.d. the predicted probability of nausea relative to placebo was 24 vs. 7% in male subjects and 40 vs. 14% in female subjects. The incidence of nausea also showed a decreasing trend with time.

Lack of a pharmacokinetic interaction between a new smoking cessation therapy, varenicline, and digoxin in adult smokers.

ObjectiveThis study investigated the effect of varenicline on the multiple-dose pharmacokinetics of digoxin.MethodsEighteen smokers were randomized to receive digoxin (Lanoxicaps® 0.2xa0mg QD) with varenicline 1xa0mg BID or placebo for 14xa0days.ResultsVarenicline had no clinically relevant effect on the digoxin steady-state exposure, as evidenced by the 90% confidence intervals for the ratios of AUC0–24 (87.5–108%) and Cmin (83.8–116%) wholly contained within 80–125%. Digoxin Cmax and Tmax remained unchanged in the presence of varenicline, consistent with no apparent alteration in digoxin bioavailability. A minimal 11.3% increase in digoxin renal clearance was noted during varenicline treatment while having no impact on its systemic exposure. Results are supported by mechanistic evidence in Caco-2 cell monolayers that varenicline is neither a P-gp substrate nor an inhibitor of P-gp-mediated efflux of digoxin. Co-administration of varenicline and digoxin was well tolerated.ConclusionThe results suggest that digoxin can be safely administered with varenicline without the need for dose adjustment.

Varenicline overdose in a teenager - a clinical pharmacology perspective

We comment here on the case report of varenicline overdosing in a teenager who ingested 30 tablets of 0.5 mg varenicline without serious adverse events and was dismissed from the hospital 8 h after admission. Data from phase 1 clinical trials showed rapid vomiting responses after high doses of varenicline. Maximum plasma concentrations after a single 10-mg dose, at which all subjects vomited, were found to range from 4.1 to 18 ng/mL, similar to those observed after a single 3-mg dose. Dose-escalating studies have consistently led to permanent discontinuation of subjects because of high incidence of early onset of vomiting. Analyses of plasma peak exposures observed following multiple days of high-dose regimens of up to 3 mg daily indicated that circulating concentrations never exceeded 28.3 ng/mL in any individual. In this overdose case, it is reasonable to expect that after acute ingestion of a single 15-mg dose, the systemic exposure of varenicline would be considerably reduced following emesis, reaching levels near those observed in healthy volunteers administered 10 mg. The highest concentration observed after a 10-mg dose, 18 ng/mL, corresponds to free levels of varenicline of approximately 70 nM that are available for interactions with the target and other receptors. At that concentration, varenicline maintains good α4β2 selectivity and is unlikely to cause nicotine-like toxicity, because it has much higher affinity for α4β2 nAChRs (Ki=0.15 nM) than for other nAChRs (Ki>86 nM) or transmitter receptors and transporters (Ki>350 nM) and lacks affinity for muscle-type α1β1δγε nAChRs (Ki>10 μM) and smooth muscle-type muscarinic AChRs (Ki>3 μM). The transient increases in blood pressure and heart rate that were described in the overdose case could be a consequence of the powerful autonomic response associated with vomiting. One possible mechanism of vomiting induced by high varenicline doses is activation of gastrointestinal 5-HT3 receptors. As varenicline is a 5-HT3A receptor agonist (EC50=1 μM), it is conceivable that immediately after ingesting high doses, gut concentrations could be high enough to allow transient activation of local 5-HT3 receptors. This mechanism would explain a rapid onset vomiting response that effectively limits systemic exposure. In summary, the most frequent adverse events of varenicline, nausea and at high doses vomiting, can act as a protection mechanism that reduces risk of overexposure when patients either accidentally or intentionally overdose.